Approximately 50% of all mammalian bioactive peptides require a C-terminal a-amide moiety for full biological activity. The C-terminal amide is produced by oxidative cleavage of a C-terminal glycine-extended pro-hormone to yield the a-amidated peptide and glyoxylate. The enzyme catalyzing this post-translational modification reaction is peptidylglycine a-amidating monooxygenase (PAM). PAM has potential as a novel therapeutic target as a consequence of the role-played by numerous alpha-amidated peptides in disease, examples being luteinizing hormone-releasing hormone (LHRH) and vasoactive intestinal peptide (VIP) in cancer, substance P in rheumatoid arthritis, and corticotropin-releasing factor (CRF) in anxiety and depression. Inhibition of PAM would generate the glycine-extended precursor that is generally >1000-fold less potent than the mature alpha-amidated peptide. However, the large number of known mammalian alpha-amidated peptides (approximately 50-100 are known) means that a drug specifically targeted against PAM is likely to be highly toxic. Disruption or elimination of the PAM gene in mice and Drosophila is lethal. As a consequence, the potential for PAM as a therapeutic target remains untapped. We propose to solve this problem in a completely new way - with the design of molecular clamp to specifically block the amidation of a single glycine-extend pro-hormone. Such an anti-amidation molecular clamp (AM-CLAMP) would not broadly inhibit PAM and, thus, would side step the serious toxicity problems associated with a general inhibition of peptide amidation.